Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) that is responsible for long-term morbidity in over 300,000 patients in the US. A great deal of our understanding about the immunologic processes that underlie MS is derived from studies in its animal model, EAE (experimental autoimmune encephalomyelitis). The vast majority of studies in MS and EAE have focused on the role of CD4+ T cells in these diseases, with the underlying assumption that MS, like classic EAE, is a CD4+ Th1-mediated autoimmune disease. As a result, most therapeutic strategies (both in the pre-clinical and clinical stages) are being focused on modulating CD4+ T cells with limited success. [unreadable] [unreadable] Recent studies from our laboratory as well as prior reports from others have provided evidence for the involvement of CD8+ T cells in the pathogenesis as well as regulation of human MS. Additionally, a role for CD8+ T cells in autoimmune demyelination has also been suggested in certain EAE models. We believe that in order to design rational therapy for this disease, it is critical to understand the functional roles of both CD8+ and CD4+ T cells in the process of autoimmune demyelination. This necessitates the development of a novel murine model wherein CD8+ T cells can induce demyelination and can be specifically dissected and targeted by different immunotherapeutic approaches. In this exploratory/developmental R21 application, we propose to develop such a model by creating a T-cell receptor transgenic mouse that expresses a CNS-reactive CD8+ T cell receptor on its T cells. We expect that the availability of such a model would impact the field by enabling the detailed dissection of the role of autoreactive CD8+ T cells; the development of intervention strategies that can specifically target these populations; and the delineation of interactions between autoreactive and/or regulatory CD4+ and CD8+ T cells. [unreadable] [unreadable]